HIV replication inhibiting pyrimidines

ABSTRACT

This invention concerns the use of compounds of formula 
                         
the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein -a 1 =a 2 -a 3 =a 4 - forms a phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl with the attached vinyl group; n is 0 to 4; and where possible 5; R 1  is hydrogen, aryl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, substituted C 1-6 alkyl, or substituted C 1-6 alkyloxyC 1-6 alkylcarbonyl; each R 2  independently is hydroxy, halo, optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkylamino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or a 5-membered heterocyclic ring; p is 1 or 2; L is optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-7 cycloalkyl; or L is —X—R 3  wherein R 3  is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; X is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or —S(═O) 2 —; Q is hydrogen, C 1-6 alkyl, halo, polyhalo-C 1-6 alkyl or an optionally substituted amino group; Y represents hydroxy, halo, C 3-7 cycloalkyl, optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 6 , —NH—S(═O) p R 6 , —C(═O)R 6 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 6 , —C(═NH)R 6  or aryl; aryl is optionally substituted phenyl; Het is an optionally substituted heterocyclic radical; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 11/930,835, filedOct. 31, 2007 now U.S. Pat. No. 8,003,789, which is a continuation ofU.S. Ser. No. 11/204,513, filed Aug. 16, 2005 now abandoned, which is acontinuation of U.S. Ser. No. 10/634,682, filed Aug. 5, 2003, now U.S.Pat. No. 7,037,917, which is a continuation of U.S. Ser. No. 09/430,966,filed Nov. 1, 1999, now U.S. Pat. No. 6,878,717, which claims priorityto applications U.S. Provisional Application No. 60/107,792, filed Nov.10, 1998 and U.S. Provisional Application No. 60/143,962, filed Jul. 15,1999 and PCT/EP1999/07417, filed Sep. 24, 1999, the entire disclosuresof which are hereby incorporated in their entirety.

The present invention concerns the use of pyrimidine derivatives havingHuman Immunodeficiency Virus (HIV) replication inhibiting properties. Italso relates to a novel group of pyrimidine derivatives, their use as amedicine, their processes for preparation and pharmaceuticalcompositions comprising them.

EP-0,834,507 discloses substituted diamino 1,3,5-triazine derivativeshaving HIV replication inhibiting properties. The present compoundsdiffer from the known 1,3,5-triazines by structure and by their improvedHIV replication inhibiting properties.

The present invention is concerned with the use of compounds of formula(I)

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines and the stereochemically isomeric forms thereof,wherein

-   -   -a¹=a²-a³=a⁴- represents a bivalent radical of formula        —CH═CH—CH═CH—  (a-1);        —N═CH—CH═CH—  (a-2);        —N═CH—N═CH—  (a-3);        —N═CH—CH═N—  (a-4);        —N═N—CH═CH—  (a-5);    -   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n        may also be 5;    -   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;        C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,        C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy;        C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with        C₁₋₆alkyloxycarbonyl;    -   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally        substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl        optionally substituted with one or more halogen atoms or cyano,        C₂₋₆alkynyl optionally substituted with one or more halogen        atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl,        cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,        polyhalomethyl, polyhalomethyloxy, polyhalomethylthio,        —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, C(═O)NHNH₂,        —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

-   -   wherein each A independently is N, CH or CR⁶;        -   B is NH, O, S or NR⁶;        -   p is 1 or 2; and        -   R⁶ is methyl, amino, mono- or dimethylamino or            polyhalomethyl;    -   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,        whereby each of said aliphatic group may be substituted with one        or two substituents independently selected from        -   C₃₋₇cycloalkyl,        -   indolyl or isoindolyl, each optionally substituted with one,            two, three or four substituents each independently selected            from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano,            aminocarbonyl, nitro, amino, polyhalomethyl,            polyhalomethyloxy and C₁₋₆alkylcarbonyl,        -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,            wherein each of said aromatic rings may optionally be            substituted with one, two, three, four or five substituents            each independently selected from the substituents defined in            R²; or    -   L is —X—R³ wherein        -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or            pyridazinyl, wherein each of said aromatic rings may            optionally be substituted with one, two, three, four or five            substituents each independently selected from the            substituents defined in R²; and        -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,            —S(═O)— or —S(═O)₂—;    -   Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or        —NR⁴R⁵; and    -   R⁴ and R⁵ are each independently selected from hydrogen,        hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,        C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or        di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl        wherein each of the aforementioned C₁₋₁₂alkyl groups may        optionally and each individually be substituted with one or two        substituents each independently selected from hydroxy,        C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl,        C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- or        di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,        polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶,        —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het; or    -   R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,        morpholinyl, azido or mono- or        di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;    -   Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl        optionally substituted with one or more halogen atoms,        C₂₋₆alkynyl optionally substituted with one or more halogen        atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶,        C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,        amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,        polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,        —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,        —C(═NH)R⁶ or aryl;    -   aryl is phenyl or phenyl substituted with one, two, three, four        or five substituents each independently selected from halo,        C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,        polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;    -   Het is an aliphatic or aromatic heterocyclic radical; said        aliphatic heterocyclic radical is selected from pyrrolidinyl,        piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,        tetrahydrofuranyl and tetrahydrothienyl wherein each of said        aliphatic heterocyclic radical may optionally be substituted        with an oxo group; and said aromatic heterocyclic radical is        selected from pyrrolyl, furanyl, thienyl, pyridinyl,        pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said        aromatic heterocyclic radical may optionally be substituted with        hydroxy;        for the manufacture of a medicine for the treatment of subjects        suffering from HIV (Human Immunodeficiency Virus) infection.

The present invention also relates to a method of treating warm-bloodedanimals suffering from HIV (Human Immunodeficiency Virus) infection.Said method comprises the administration of a therapeutically effectiveamount of a compound of formula (I) or a N-oxide form, apharmaceutically acceptable addition salt or a stereochemically isomericform thereof in admixture with a pharmaceutical carrier.

This invention also relates to novel compounds having the formula

the N-oxides, the addition salts, the quaternary amines and thestereochemically isomeric forms thereof, wherein

-   -   -b¹=b²-C(R^(2a))=b³-b⁴= represents a bivalent radical of formula        —CH═CH—C(R^(2a))═CH—CH═  (b-1);        —N═CH—C(R^(2a))═CH—CH═  (b-2);        —CH═N—C(R^(2a))═CH—CH═  (b-3);        —N═CH—C(R^(2a))═N—CH═  (b-4);        —N═CH—C(R^(2a))═CH—N═  (b-5);        —CH═N—C(R^(2a))═N—CH═  (b-6);        —N═N—C(R^(2a))═CH—CH═  (b-7);    -   q is 0, 1, 2; or where possible q is 3 or 4;    -   R¹ is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;        C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,        C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy,        C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted with        C₁₋₆alkyloxycarbonyl    -   R^(2a) is cyano, aminocarbonyl, mono- or        di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano,        aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl        substituted with cyano, or C₂₋₆alkynyl substituted with cyano;    -   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally        substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl        optionally substituted with one or more halogen atoms or cyano,        C₂₋₆alkynyl optionally substituted with one or more halogen        atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl,        cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,        polyhalomethyl, polyhalomethyloxy, polyhalomethylthio,        —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂,        —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

-   -   wherein each A independently is N, CH or CR⁶;        -   B is NH, O, S or NR⁶;        -   p is 1 or 2; and        -   R⁶ is methyl, amino, mono- or dimethylamino or            polyhalomethyl;    -   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl,        whereby each of said aliphatic group may be substituted with one        or two substituents independently selected from        -   C₃₋₇cycloalkyl,        -   indolyl or isoindolyl, each optionally substituted with one,            two, three or four substituents each independently selected            from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano,            aminocarbonyl, nitro, amino, polyhalomethyl,            polyhalomethyloxy and C₁₋₆alkylcarbonyl,        -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,            wherein each of said aromatic rings may optionally be            substituted with one, two, three, four or five substituents            each independently selected from the substituents defined in            R²; or    -   L is —X—R³ wherein        -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or            pyridazinyl, wherein each of said aromatic rings may            optionally be substituted with one, two, three, four or five            substituents each independently selected from the            substituents defined in R²; and        -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,            —S(═O)— or —S(═O)₂—;    -   Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or        —NR⁴R⁵; and    -   R⁴ and R⁵ are each independently selected from hydrogen,        hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,        C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or        di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl        wherein each of the aforementioned C₁₋₁₂alkyl groups may        optionally and each individually be substituted with one or two        substituents each independently selected from hydroxy,        C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl,        C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- or        di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,        polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶,        —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het; or    -   R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,        morpholinyl, azido or mono- or        di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;    -   Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl        optionally substituted with one or more halogen atoms,        C₂₋₆alkynyl optionally substituted with one or more halogen        atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶,        C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,        amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,        polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,        —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,        —C(═NH)R⁶ or aryl;    -   aryl is phenyl or phenyl substituted with one, two, three, four        or five substituents each independently selected from halo,        C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro,        polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;    -   Het is an aliphatic or aromatic heterocyclic radical; said        aliphatic heterocyclic radical is selected from pyrrolidinyl,        piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,        tetrahydrofuranyl and tetrahydrothienyl wherein each of said        aliphatic heterocyclic radical may optionally be substituted        with an oxo group; and said aromatic heterocyclic radical is        selected from pyrrolyl, furanyl, thienyl, pyridinyl,        pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said        aromatic heterocyclic radical may optionally be substituted with        hydroxy.

As used herein C₁₋₆alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 6carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl,pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C₁₋₁₀alkyl asa group or part of a group defines straight or branched chain saturatedhydrocarbon radicals having from 1 to 10 carbon atoms such as the groupsdefined for C₁₋₆alkyl and heptyl, octyl, nonyl, decyl and the like;C₁₋₁₂alkyl as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 12 carbon atomssuch as the groups defined for C₁₋₁₀alkyl and undecyl, dodecyl and thelike; C₁₋₄alkylidene defines straight or branched chain saturatedbivalent hydrocarbon radicals having from 1 to 4 carbon atoms such asmethylene, 1,2-ethanediyl or 1,2-ethylidene, 1,3-propanediyl or1,3-propylidene, 1,4-butanediyl or 1,4-butylidene and the like;C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms containing adouble bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl andthe like; C₂₋₁₀alkenyl defines straight and branched chain hydrocarbonradicals having from 2 to 10 carbon atoms containing a double bond suchas the groups defined for C₂₋₆alkenyl and heptenyl, octenyl, nonenyl,decenyl and the like; C₂₋₆alkynyl defines straight and branched chainhydrocarbon radicals having from 2 to 6 carbon atoms containing a triplebond such as ethynyl, propynyl, butyryl, pentynyl, hexynyl and the like;C₂₋₁₀alkynyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 10 carbon atoms containing a triple bond such as thegroups defined for C₂₋₆alkynyl and heptynyl, octynyl, nonynyl, decynyland the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide group when attached once to asulfur atom, and a sulfonyl group when attached twice to a sulfur atom.

The term halo is generic to Nora, chloro, bromo and iodo. As used in theforegoing and hereinafter, polyhalomethyl as a group or part of a groupis defined as mono- or polyhalosubstituted methyl, in particular methylwith one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in halomethyl, 1,1-difluoro-ethyl and the like. In casemore than one halogen atoms are attached to an alkyl group within thedefinition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the sameor different.

Het is meant to include all the possible isomeric forms of theheterocycles mentioned in the definition of Het, for instance, pyrrolylalso includes 2H-pyrrolyl.

The Het radical may be attached to the remainder of the molecule offormula (I) or (I-a) through any ring carbon or heteroatom asappropriate. Thus, for example, when the heterocycle is pyridinyl, itmay be 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.

When any variable (eg. aryl, R², R⁶ etc.) occurs more than one time inany constituent, each definition is independent.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the suitable ring atoms.

It will be appreciated that some of the compounds of formula (I) or(I-a) and their N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula (I)or (I-a), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) or (I-a) and their N-oxides, salts, solvates or quaternaryamines substantially free, i.e. associated with less than 10%,preferably less than 5%, in particular less than 2% and most preferablyless than 1% of the other isomers. In particular, stereogenic centersmay have the R- or S-configuration; substituents on bivalent cyclic(partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an Eor Z-stereochemistry at said double bond. Stereochemically isomericforms of the compounds of formula (I) or (I-a) are obviously intended tobe embraced within the scope of this invention.

For therapeutic use, salts of the compounds of formula (I) or (I-a) arethose wherein the counterion is pharmaceutically acceptable. However,salts of acids and bases which are not pharmaceutically acceptable mayalso find use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) or (I-a) are able to form. The pharmaceutically acceptableacid addition salts can conveniently be obtained by treating the baseform with such appropriate acid. Appropriate acids comprise, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butanedioic acid), maleic, fumaric, malic, tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be convened by treatment with anappropriate base into the free base form.

The compounds of formula (I) or (I-a) containing an acidic proton mayalso be converted into their non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) or (I-a) as well as the saltsthereof, are able to form. Such solvates are for example hydrates,alcoholates and the like.

Some of the compounds of formula (I) or (I-a) may also exist in theirtautomeric form. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term “compounds of formula (I)” or“compounds of formula (I-a)” is meant to include also the N-oxides, theaddition salts, the quaternary amines and all stereoisomeric forms.

A special group of compounds contains those compounds of formula (I)wherein R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl.

Another special group of compounds contains those compounds of formula(I) wherein one or more of the following restrictions apply:

-   -   i) -a¹=a²-a³=a⁴- is a radical of formula (a-1);    -   ii) R¹ is hydrogen;    -   iii) n is 1;    -   iv) R² is cyano, preferably in the para position relative to the        —NR¹— group;    -   v) Y is cyano, —C(═O)NH₂ or a halogen, preferably a halogen;    -   vi) Q is hydrogen or —NR⁴R⁵ wherein R⁴ and R⁵ are preferably        hydrogen;    -   vii) L is —X—R³ wherein X is preferably NR¹, O or S, most        preferably X is NH, and R³ is substituted phenyl with C₁₋₆alkyl,        halogen and cyano as preferred substituents.

Still another special group of compounds contains those compounds offormula (I-a) wherein R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl.

Another special group of compounds contains also those compounds offormula (I-a) wherein one or more of the following restrictions apply:

-   -   i) -b¹=b²-C(R^(2a))=b³-b⁴= is a radical of formula (b-1);    -   ii) q is 0;    -   iii) R^(2a) is cyano or —C(═O)NH₂, preferably R^(2a) is cyano;    -   iv) Y is cyano, —C(═O)NH₂ or a halogen, preferably a halogen;    -   v) Q is hydrogen or —NR⁴R⁵ wherein R⁴ and R⁵ are preferably        hydrogen;    -   vi) L is —X—R³ wherein X is preferably NR¹, O or S, most        preferably X is NH, and R³ is substituted phenyl with C₁₋₆alkyl,        halogen and cyano as preferred substituents.

An interesting group of compounds are those compounds of formula (I) or(I-a) wherein L is —X—R³ wherein R³ is 2,4,6-trisubstituted phenyl, eachsubstituent independently selected from chloro, bromo, fluoro, cyano orC₁₋₄alkyl.

Also interesting are those compounds of formula (I) or (I-a) wherein Yis chloro or bromo and Q is hydrogen or amino.

Particular compounds are those compounds of formula (I) or (I-a) whereinthe moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilinogroup.

Preferred compounds are those compounds of formula (I) or (I-a) whereinthe moiety in the 2 position of the pyrimidine ring is a 4-cyano-anilinogroup, L is —X—R³ wherein R³ is a 2,4,6-trisubstituted phenyl, Y is ahalogen and Q is hydrogen or NH₂.

Most preferred compounds are:

-   4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;-   4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile;    and-   4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidyl]amino]benzonitrile;    the N-oxides, the addition salts, the quaternary amines and the    stereochemically isomeric forms thereof.

In general, compounds of formula (I-a) can be prepared by reacting anintermediate of formula (II) wherein W¹ is a suitable leaving group suchas, for example, a halogen, hydroxy, triflate, tosylate, thiomethyl,methylsulfonyl, trifluoromethylsulfonyl and the like, with an aminoderivative of formula (III) optionally under solvent-free conditions orin a reaction-inert solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of an acidsuch as, for example, 1 N hydrochloric acid in diethyl ether or thelike. This reaction can be performed at a temperature ranging between50° C. and 250° C.

In this and the following preparations, the reaction products may beisolated from the reaction medium and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, crystallization, distillation, trituration andchromatography.

The compounds of formula (I-a) wherein L is a radical of formula—NR¹—R³, said compounds being represented by formula (I-a-1), can beprepared by reacting an intermediate of formula (IV) wherein W² is asuitable leaving group such as, for example, a halogen or a triflate,with an intermediate of formula (V) under solvent-free conditions or inan appropriate solvent such as, for example, ethanol,1-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dioxane,tetrahydrofuran, dimethyl sulfoxide, tetraline, sulfolane, acetonitrileand the like, under a reaction-inert atmosphere such as, for example,oxygen free argon or nitrogen, and optionally in the presence of an acidsuch as, for example, 1 N hydrochloric acid in diethyl ether. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

The compounds of formula (I-a) wherein L is a radical of formula —O—R³,said compounds being represented by formula (I-a-2), can be prepared byreacting an intermediate of formula (IV) wherein W² is a suitableleaving group such as, for example a halogen or a triflate, with anintermediate of formula (VI) in an appropriate solvent such as, forexample, 1,4-dioxane, dimethyl sulfoxide, tetraline, sulfolane and thelike under a reaction-inert atmosphere such as, for example, oxygen freeargon or nitrogen, and in the presence of a base such as, for example,sodium hydride, potassium hydride, sodium hydroxide or the like. Thisreaction can be performed at a temperature ranging between 50° C. and250° C.

The compounds of formula (I-a) may further be prepared by convertingcompounds of formula (I-a) into each other according to art-known grouptransformation reactions.

The compounds of formula (I-a) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I-a) withan appropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

For instance, the compounds of formula (I-a) wherein Q is a halogen maybe converted to the corresponding compounds wherein Q is —NR⁴H usingNH₂R⁴ as a reagent in a reaction inert solvent such as, for example,1,4-dioxane and the like, optionally in the presence of a suitable basesuch as, for example, triethylamine or N,N-diisopropylethylamine or thelike. In case R⁴ contains a hydroxy moiety, it may be convenient toperform the above reaction with a protected form of NH₂R⁴ whereby thehydroxy moiety bears a suitable protecting group P being, for instance,a trialkylsilyl group, and subsequently removing the protective groupaccording to art-known methodologies.

Some of the compounds of formula (I-a) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I-a) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II) wherein L is —X—R³, said intermediatesbeing represented by formula (II-1) can be prepared by reacting apyrimidine derivative of formula (VII) wherein each W¹ is as definedpreviously, with HXR³ (VIII) in a reaction inert solvent such as, forexample, 1,4-dioxane, 2-propanol or the like, and in the presence of abase such as, for example, triethylamine or N,N-diisopropylethylamine orthe like. Different regio-specific isomers may be formed and can beseparated from one another using suitable separation techniques such as,for example, chromatography.

Intermediates of formula (IV) can be prepared by reacting anintermediate of formula (VII-a) wherein W² is a suitable leaving groupsuch as, for example, a halogen, with an intermediate of formula (IX) ina suitable solvent such as, for example, 1-methyl-2-pyrrolidinone,1,4-dioxane or the like, in the presence of an acid such as, forexample, 1 N hydrochloric acid in diethyl ether. This reaction can beperformed at a temperature ranging between 50° C. and 250° C.

Alternatively, intermediates of formula (IV) can be prepared by reactingan intermediate of formula (X) with phosphorous oxychloride, triflicanhydride or a functional derivative thereof under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen. Thisreaction can be performed at a temperature ranging between 20° C. and150° C.

Intermediates of formula (X) can be prepared by reacting an intermediateof formula (XI) or a functional derivative thereof, with an intermediateof formula (IX). This reaction may be performed under solvent-freeconditions or in an appropriate solvent such as, for example, diglyme,tetraline or the like under a reaction-inert atmosphere such as, forexample, oxygen free argon or nitrogen, and optionally in the presenceof a base such as, for example, sodium hydride, potassium hydride or thelike. This reaction can be performed at a temperature ranging between100° C. and 250° C.

Intermediates of formula (X) can also be prepared by reacting anintermediate of formula (XII), wherein W² is a suitable leaving groupand Y and Q are as defined for a compound of formula (I-a), with anintermediate of formula (XIII) in an appropriate solvent such as, forexample, ethanol, or the like, and in the presence of a base such as,for example, sodium ethoxide or the like, under a reaction-inertatmosphere such as, for example, oxygen free argon or nitrogen. Thereaction can be performed at a temperature ranging between 20° C. and125° C.

A convenient way of preparing an intermediate of formula (IV) wherein Yis a bromine or chloro atom, said intermediates being represented byformula (IV-1), involves the introduction of a bromine or chloro atom toan intermediate of formula (XIV), wherein W² is as previously defined,using N-bromosuccinimide or N-chlorosuccinimide in a reaction-inertsolvent such as, for example, chloroform, carbon tetrachloride or thelike. This reaction can be performed at a temperature ranging between20° C. and 125° C.

Analogous to the conversion of compounds of formula (I-a) wherein Q is ahalogen to compounds of formula (I-a) wherein Q is —NHR⁴, theintermediates of formula (II), (IV) and (VII) can also be converted.

The compounds of formula (I-a) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I-a) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I-a)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

The compounds of formula (I) and (I-a) show antiretroviral properties,in particular against Human Immunodeficiency Virus (HIV), which is theaetiological agent of Acquired Immune Deficiency Syndrome (AIDS) inhumans. The HIV virus preferentially infects human T-4 cells anddestroys them or changes their normal function, particularly thecoordination of the immune system. As a result, an infected patient hasan everdecreasing number of T-4 cells, which moreover behave abnormally.Hence, the immunological defense system is unable to combat infectionsand neoplasms and the HIV infected subject usually dies by opportunisticinfections such as pneumonia, or by cancers. Other conditions associatedwith HIV infection include thrombocytopaenia, Kaposi's sarcoma andinfection of the central nervous system characterized by progressivedemyelination, resulting in dementia and symptoms such as, progressivedysarthria, ataxia and disorientation. HIV infection further has alsobeen associated with peripheral neuropathy, progressive generalizedlymphadenopathy (PGL) and AIDS-related complex (ARC).

The present compounds also show activity against HIV-1 strains that haveacquired resistance to art-known non-nucleoside reverse transcriptaseinhibitors. They also have little or no binding affinity to human α-1acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I) or (I-a), their N-oxides, pharmaceutically acceptableaddition salts, quaternary amines and stereochemically isomeric formsthereof, are useful in the treatment of individuals infected by HIV andfor the prophylaxis of these infections. In general, the compounds ofthe present invention may be useful in the treatment of warm-bloodedanimals infected with viruses whose existence is mediated by, or dependsupon, the enzyme reverse transcriptase. Conditions which may beprevented or treated with the compounds of the present invention,especially conditions associated with HIV and other pathogenicretroviruses, include AIDS, AIDS-related complex (ARC), progressivegeneralized lymphadenopathy (PGL), as well as chronic CNS diseasescaused by retroviruses, such as, for example HIV mediated dementia andmultiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

To aid solubility of the compounds of formula (I-a), suitableingredients, e.g. cyclodextrins, may be included in the compositions.Appropriate cyclodextrins are α-, β-, γ-cyclodextrins or ethers andmixed ethers thereof wherein one or more of the hydroxy groups of theanhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl,particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles obtainable by melt-extruding a mixture comprising a compoundof formula (I-a) and an appropriate water-soluble polymer andsubsequently milling said melt-extruded mixture. Said particles can thenbe formulated by conventional techniques into pharmaceutical dosageforms such as tablets and capsules.

Said particles consist of a solid dispersion comprising a compound offormula (I-a) and one or more pharmaceutically acceptable water-solublepolymers. The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I-a) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating the thus obtained blend until one obtains a        homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt till it solidifies.

The solid dispersion product is milled or ground to particles having aparticle size of less than 1500 μm, preferably less than 400 μm, morepreferably less than 250 μm and most preferably less than 125 μm.

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa·s, more preferably of 1 to 700 mPa·s, andmost preferred of 1 to 100 mPa·s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates,polysaccharides, polyacrylic acids and the salts thereof,polymethacrylic acids and the salts and esters thereof, methacrylatecopolymers, polyvinylalcohol, polyalkylene oxides and copolymers ofethylene oxide and propylene oxide. Preferred water-soluble polymers areEudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins which can be used include polyethers describedin U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are etherswherein the hydrogen of one or more cyclodextrin hydroxy groups isreplaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

A more novel type of substituted cyclodextrins issulfobutylcyclodextrines.

The ratio of the compound of formula (I-a) over cyclodextrin may varywidely. For example ratios of 1/100 to 100/1 may be applied. Interestingratios of the compound of formula (I-a) over cyclodextrin range fromabout 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I-a)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of thecompound of formula (I-a) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula(I-a) involves a pharmaceutical composition whereby the compounds offormula (I-a) are incorporated in hydrophilic polymers and applying thismixture as a coat film over many small beads, thus yielding acomposition which can conveniently be manufactured and which is suitablefor preparing pharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I-a) and aseal-coating polymer layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) or (I-a) used, the particularcondition being treated, the severity of the condition being treated,the age, weight and general physical condition of the particular patientas well as other medication the individual may be taking, as is wellknown to those skilled in the art. Furthermore, it is evident that saideffective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines and are not intended to limit the scope or use of theinvention to any extent.

Also, the combination of an antiretroviral compound and a compound offormula (I) or (I-a) can be used as a medicine. Thus, the presentinvention also relates to a product containing (a) a compound of formula(I) or (I-a), and (b) another antiretroviral compound, as a combinedpreparation for simultaneous, separate or sequential use in anti-HIVtreatment. The different drugs may be combined in a single preparationtogether with pharmaceutically acceptable carriers. Said otherantiretroviral compounds may be known antiretroviral compounds such asnucleoside reverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI),zalcitabine (dideoxycytidine, ddC) or lamivudine(3′-thia-2′-3′-dideoxycytidine, 3TC) and the like; non-nucleosidereverse transcriptase inhibitors such as suramine, pentamidine,thymopentin, castanospermine, efavirenz, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one),tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO(tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitro-phenyl)amino]-2,6-dichlorobenzene-acetamide and the like;TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g.indinavir, ritanovir, saquinovir, ABT-378 and the like; orimmunomodulating agents, e.g. levamisole and the like. The compound offormula (I) or (I-a) can also be combined with another compound offormula (I) or (I-a).

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART A. Preparation of the Intermediate Compounds ExampleA1

Reaction under argon atmosphere. A solution of2,4,6-trimethylbenzenamine (0.00461 mol) in 1,4-dioxane (5 ml) was addedto a solution of 5-bromo-2,4-dichloropyrimidine (0.00439 mol) in1,4-dioxane (5 ml). N,N-bis(1-methylethyl)ethanamine (0.00548 mol) wasadded. The reaction mixture was stirred and refluxed for 20 hours. Thesolvent was evaporated. The residue was dissolved in ethyl acetate,washed with a saturated aqueous sodium bicarbonate solution, water andbrine, dried with sodium sulfate, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: 1:5, 1:2 and 1:1 CH₂Cl₂:hexane). Two pure fractiongroups were collected and their solvent was evaporated, yielding 0.35 g(24%) of 5-bromo-4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine(interm. 1) and 0.93 g (65%) of5-bromo-2-chloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine (interim 2).

Example A2

a) 4-Hydroxy-5-chloro-2-methylthiopyrimidine (0.0156 mol) and4-aminobenzonitrile (0.078-mol) were combined as a melt and stirred at180-200° C. for 6 hours. The reaction mixture was cooled, and trituratedsequentially with boiling CH₂Cl₂ and CH₃CN to obtain 95% pure compound,which was dried, yielding 1.27 g (33%) of4-[(5-chloro-4-hydroxy-2-pyrimidinyl)amino]benzonitrile (interm. 3;mp. >300° C.).

b) POCl₃ (10 ml) was added to intermediate (3) (0.0028 mol). The flaskwas equipped with a condenser and heated to 80° C. for 35 minutes. Thematerial was quenched on ice and allowed and the resulting precipitatewas collected and washed with water (50 ml). The sample was dried. Afraction thereof was further purified by column chromatography. The purefractions were collected and the solvent was evaporated, yielding4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrile (interim 4).

c) The mixture of intermediate (4) (0.0132 mol) in tetrahydrofuran (75ml) and CH₂Cl₂ (10 ml) was stirred for 15 min. HCl in diethyl ether(0.0145 mop was added slowly, and the mixture was stirred for 5 minutes.The solvent was removed under reduced pressure, yielding 3.98 g of4-[(4,5-dichloro-2-pyrimidinyl)amino]benzonitrile monohydrochloride(interim 5).

Example A3

a) 2,4,5,6-tetrachloropyrimidine (0.0134 mol), 1,4-dioxane (30 ml),2,4,6-trimethyl aniline (0.0134 mol), andN,N-bis(1-methylethyl)ethanamine (0.0136 mol) were added to a flaskunder argon and stirred at 55° C. for 16 hours. The solvent wasevaporated, and the residue was dissolved in CH₂Cl₂, then purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/hexane ¼, and ½).The desired fractions were collected and their solvent was evaporated,yielding 0.15 g4,5,6-trichloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 6)and 3.15 g 2,5,6-trichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine(interm. 7).

b) A mixture of intermediate 7 (0.00474 mol) in NH₃, (2.0 M in2-propanol; 20 ml) was heated in a pressure vessel at 75-80° C. for 40hours. The temperature was increased to 110-115° C. The solvent wasevaporated to produce 1.85 g of residue. The sample was heated with NH₃,(0.5 M in 1,4-dioxane; 20 ml) at 125° C. for 18 hours. The solvent wasevaporated, yielding 1.7 g of a mixture of two isomers, i.e.2,5-dichloro-N4-(2,4,6-trimethylphenyl)-4,6-pyrimidinediamine (interm.8) and 5,6-dichloro-N4-(2,4,6-trimethylphenyl)-2,4-pyrimidinediamine(interm. 9).

Example A4

a) A mixture of 4-[(1,4-dihydro-4-oxo-2-pyrimidinyl)amino]benzonitrile,(0.12 mol) in POCl₃ (90 ml) was stirred and refluxed under Argon for 20minutes. The reaction mixture was slowly poured onto 750 ml ice/water,and the solid was separated by filtration. The solid was suspended in500 ml water, and the pH of the suspension was adjusted to neutral byadding a 20% NaOH solution. The solid was again separated by filtration,suspended in 200 ml 2-propanone, and 1000 ml CH₂Cl₂ was added. Themixture was heated until all solid had dissolved. After cooling to roomtemperature, the aqueous layer was separated, and the organic layer wasdried. During removal of the drying agent by filtration, a white solidformed in the filtrate. Further cooling of the filtrate in the freezer,followed by filtration, yielded 21.38 g (77.2%) of4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 10).

b) Intermediate (10) (0.005 mol), 1-bromo-2,5-pyrrolidinedione (0.006mol) and trichloromethane (10 ml) were combined in a sealed tube andheated at 100° C. overnight. The reaction mixture was allowed to cool toroom temperature. Silica gel (2 g) was added, and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent: CH₂Cl₂/hexanes 9/1). The pure fractions werecollected and the solvent was evaporated, yielding 1.31 g (84.5%) of4-[(5-bromo-4-chloro-2-pyrimidinyl)amino]benzonitrile (interm. 11).

Example A5

To a flask under Argon was added 4-amino-2,5,6-trichloropyrimidine(0.08564 mol), 4-amino-benzonitrile (0.1071 mol),1-methyl-2-pyrrolidinone (17 ml) and HCl in diethylether (1M; 85.6 ml).The mixture was placed in an oil bath at 130° C. under a stream ofnitrogen until the ether was gone. An additional 10 ml of1-methyl-2-pyrrolidinone was added. The mixture was heated at 145° C.for 16 hours under argon. 1,4-Dioxane was added. The mixture wasrefluxed, cooled, then filtered. The filtrate was evaporated. Theresidue was dissolved in CH₂Cl₂, washed with 1 N NaOH, then filtered.The solid was dissolved in 2-propanone, evaporated onto silica gel, andchromatographed using 1-3% 2-propanone in hexane as eluent. The purefractions were collected and the solvent was evaporated, yielding 1.63 g(6.8%) of 4-[(4-amino-5,6-dichloro-2-pyrimidinyl)amino]benzonitrile(interm. 12).

B. Preparation of the Final Compound Example B1

a) To a flask under argon containing intermediate (1) (0.00107 mol) wasadded ether. To this homogeneous solution was added HCl/diethylether(1M; 0.00109 mol). The solvent was evaporated and 1,4-dioxane (35 ml)and 4-aminobenzonitrile (0.00322 mol) were added. The reaction mixturewas stirred and refluxed for 4 days. The solvent was evaporated. Theresidue was dissolved in CH₂Cl₂, washed with a saturated sodiumbicarbonate solution, dried, filtered and the solvent was evaporated togive 0.79 g of amber oil. The oil was purified by reverse phase HPLC.The desired fractions were collected and the solvent was evaporated,yielding residues 1 and 2.

Residue 1 was purified by column chromatography over silica gel (eluent:0 and 2% CH₃OH:CH₂Cl₂). The pure fractions were collected and thesolvent was evaporated, yielding 0.0079 g (2.0%) of4-[[5-chloro-2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile(compound 1).

Residue 2 was purified by column chromatography over silica gel (eluent:0 and 2% CH₃OH:CH₂Cl₂). The pure fractions were collected and thesolvent was evaporated, yielding 0.0044 g (1.0%) of4-[[5-bromo-2-[(2,4,6-trimethylphenyl)amino]-4-pyrimidinyl]amino]benzonitrile(compound 2).

b) To a flask containing intermediate 2 (0.00285 mop was added ether. Tothis homogeneous solution was added HCl in diethyl ether (1M; 0.00855mol). The solvent was evaporated and 1,4-dioxane (20 ml) was added.Finally, 4-aminobenzonitrile (0.00291 mol) and 1,4-dioxane (15 ml) wereadded and the reaction mixture was stirred and refluxed for seven days.The solvent was evaporated, the residue dissolved in CH₂Cl₂, washed with1 M NaOH, and the solvent evaporated. The residue was dissolved inCH₂Cl₂ (10 ml) and the precipitate was filtered off and dried, yielding0.15 g (13%) of4-[[5-bromo-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 3).

Example B2

a) A 3:1 mixture of intermediate (8) and intermediate (9) [as preparedin example A3b] and 4-aminobenzonitrile (0.01422 mol) was heated in apressure vessel at 180° C. for 5 hours. The sample was partitionedbetween CH₂Cl₂ and diluted NaHCO₃, dried over K₂CO₃, filtered, andevaporated. CH₃CN was stirred in, the resulting precipitate removed byfiltration. The filtrate was further purified by reverse phase HPLC. Thepure fractions were collected and the solvent was evaporated, yielding0.17 g of4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitriletrifluoroacetate (1:1) (comp. 4).

Example B3

HCl in diethylether (1M; 0.0045 mol) was added to a suspension ofintermediate (4) (0.003 mol) in 1,4-dioxane (5 ml), stirred under argonin a sealable tube. The mixture was warmed to evaporate thediethylether, and 2,4,6-trimethylbenzenamine (0.009 mol) was added. Thetube was sealed, and the reaction mixture was heated to 150° C. for 12hours. The reaction mixture was allowed to cool to room temperature.Sequentially, silica gel (2.2 g) and CH₃OH (50 ml) were added. Afterevaporating the solvent, the residue was purified by flashchromatography (eluent gradient: CH₂Cl₂:CH₃OH:NH₄OH 99.5:0.45:0.05 up to99:0.9:0.1). The pure fractions were collected and the solvent wasevaporated. The residue was dried, yielding 0.80 g (73.4%) of4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp. 5).

Example B4

A mixture of intermediate (5) (0.0025 mol) and2,6-dibromo-4-methylbenzenamine (0.0075 mol) in 1,3-dioxane (5.0 ml) ina sealed tube under argon was heated and stirred at 160° C. for 16hours. The reaction mixture was concentrated by rotary evaporation ontosilica gel (2.0 g). The material was purified by flash chromatography(eluent 1:1 hexanes:CH₂Cl₂; neat CH₂Cl₂; 0.5%, 1% (10% NH₄OH in CH₃OH)in CH₂Cl₂) for 90% purity. Recrystallization afforded 0.15 g (12.2%) of4-[[5-chloro-4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(comp, 10; 95% purity).

Example B5

NaH (0.0075 mol; 60% suspension in oil) was added to a suspension of2,4,6-trimethylphenol (0.0075 mol) in 1,4-dioxane (5 ml) in a sealabletube under argon. The mixture was stirred for 15 minutes, andintermediate (4) (0.0025 mol) was added. The tube was sealed, and thereaction mixture was heated to 150° C. for 15 hours. The reaction wasallowed to cool to room temperature. After silica gel (2.0 g) was added,the solvent was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent gradient: CH₂Cl₂:hexanes 9:1 upto 100:0; then CH₂Cl₂:CH₃OH:NH₄OH 100:0:0 up to 97:2.7:0.3). The purefractions were collected and the solvent was evaporated. The residue wasdried, yielding 0.73 g of (80.2%)4-[[5-chloro-4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(comp. 6).

Example B6

a) NaH, 60% suspension in oil (0.003 mol) and 1-methyl-2-pyrrolidinone(3 ml) were added to a suspension of 4-hydroxy-3,5-dimethylbenzonitrile(0.003 mol) in 1,4-dioxane (3 ml) in a sealable tube under argon. Afterthe H₂ had evolved, intermediate (11) (0.001 mol) was added. The tubewas sealed and the reaction mixture was heated to 160° C. for 16 hours.The mixture was cooled to room temperature, transferred to a beaker anddiluted with methanol (20 ml). Water (200 ml) was added dropwise. Theaqueous mixture was extracted with CH₂Cl₂/CH₃OH 90/10 (3×300 ml). Theorganic layer was separated, dried, filtered and adsorbed onto silicagel (1 g). The solvent was evaporated and the residue was purified byflash column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OHfrom 100/0/0 to 98/1.8/0.2). The desired fractions were collected andthe solvent was evaporated. The residue was triturated with hot CH₃CN,filtered off, then dried, yielding 0.20 g (47.6%) of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(comp. 17).

b) n-Butyllithium (0.010 mol) was added to a solution ofN-(1-methylethyl)-2-propanamine (0.010 mol) in tetrahydrofuran (250 ml),stirred at 0° C. After stirring cold for 30 min, compound (17) (0.005mol) was added. The resulting mixture was stirred cold for 15 min atwhich point ethyl 2-bromoethanoate (0.015 mol) was added and thetemperature was allowed to rise to room temperature and the reactionmixture was stirred for 16 hours which drove the reaction to 50%completion. Quenched with 0.5 ml H₂O, the sample was concentrated byrotary evaporation onto silica gel, and purified by flash chromatography(Biotage Flash 40M, eluting with 0, 0.5, 1% (10% NH₄OH in CH₃OH) inCH₂Cl₂) to give a white solid which was 1:1 starting material A:product.Preparatory HPLC purification eluting into tubes containing 1 mmolNaHCO₃ effected final purification. Lyophilized material was taken up inwater/CH₂Cl₂ (1:1 (50 ml total)) and separated. The aqueous phase wasextracted 2 more times with 25 ml CH₂Cl₂. The organic layers werecombined and dried over sodium sulfate, filtered and rotary evaporatedto white solid dried in vacuo at 65° C. 18 hours. Yield: 0.33 g of

(13%, white solid); mp. 185-190° C. (comp. 59).

c) Reaction under Ar flow. NaH 60% (0.00600 mol) was stirred intetrahydrofuran (20 ml). Compound (17) (0.00476 mol) was added and themixture was stirred for 15 min. Chloromethyl-2,2-dimethylpropanoate(0.00600 mol) was added and the reaction mixture was stirred for 16hours at room temperature, then stirred and refluxed for 4.5 hours, thencooled. Tetrahydrofuran (20 ml) was added. NaH 60% (0.00600 mol) andchloromethyl-2,2-dimethylpropanoate (0.00600 mol) were added and theresulting reaction mixture was stirred for 24 hours. The solvent wasevaporated. The residue was dissolved in CH₂Cl₂, washed with water, andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 and99.5/0.5). The desired fractions were collected and the solvent wasevaporated. The residue was purified on the Gilson. This fraction wascrystallized from 2-propanol, filtered off and dried. Yield: 0.60 g of

(23.6%, white solid) (comp. 60).

d) A suspension of compound (17) (0.0020 mol) in tetrahydrofuran (40 ml)was treated with 0.24 g of NaH in one portion. The effervescent mixturewas stirred for 2 hours to afford a bright yellow suspension. A solutionof 2,2′-oxybisacetyl chloride (0.020 mol) in tetrahydrofuran (10 ml) wasprepared and cooled in an ice bath. Via cannula, the resultant A/Bsuspension was transferred to the cold solution of 2,2′-oxybisacetylchloride dropwise over 10 minutes. The mixture was warmed to roomtemperature and stirred for 3 days. Another 0.24 g of NaH was added andafter 2 days the reaction was cooled in an ice bath and treated with amixture of methanol (0.150 mol) and N,N-diethylethanamine (0.150 mol)dropwise over 30 minutes. The reaction mixture was warmed to roomtemperature and after 16 hours poured into ether and extracted withsaturated NaHCO₃. The aqueous fraction was extracted 2× with ether andthe combined ether extracts were backwashed 3× with water and dried overMgSO₄. Concentration afforded 2.91 g of an oily residue that wassubjected to reverse phase prep HPLC. Lyophilization of the appropriatefractions provided 0.16 g of the

sample as a beige powder (14.5% purified yield) (comp. 61).

Example B7

To a pressure vessel under argon was added intermediate 12 (0.00286mol), 4-cyano-2,6-dimethylaniline (0.00571 mol), 1M HCl in diethyl ether(0.00140 mol) and 1,4-dioxane (8 ml). The reaction mixture was heated inan oil bath under a stream of nitrogen until all the solvents hadevaporated. 1-methyl-2-pyrrolidinone (3 ml) was added, and the reactionmixture heated at 220-240° C. for 3 hours. Heating was continued at210-220° C. for 6 hours. The residue was dissolved in 1,4-dioxane,evaporated, partitioned between CH₂Cl₂ and 1 N NaOH, filtered, driedorganic layers with potassium carbonate and evaporated. The desiredcompound was isolated and purified by preparative reverse phasechromatography. The pure fractions were collected and the solvent wasevaporated, yielding 0.0165 g (1.1% after lyophilization) of4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitriletrifluoroacetate (1:1) (comp. 19).

Example B8

A mixture of intermediate (11) (0.0011 mol),2,6-dimethyl-4-(2-propyl)benzenamine (0.0011 mol),N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.0022 mol) and 1 M HCl inether (2.3 ml) (0.0023 mol) in 1,4-dioxane (25 ml) was stirred andheated to 95° C. for 16 hours. Solvent was removed by rotary evaporationand the residue was purified by reverse phase preparatory HPLC. Thecombined fractions containing the desired material were lyophilized toyield 0.23 g of

(48%); mp. 198-201° C. (comp. 40)

Example B9

N,N-di(methylethyl)ethanamine (0.0024 mol) was added to4-amino-2,5-dimethyl-3,4-benzonitrile (0.00219 mol) and4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (0.00218mol). The reaction vial was sealed and heated to 155-160° C. withstirring for 1.5 days. The sample was cooled to room temperature. Thesample was treated with flash column chromatography over silica gel(eluent: CH₂Cl₂). Purification was completed through preparative HPLC toyield 0.05 g of4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(5.0%); mp. 259-260° C. (comp. 42).

Example B10

Sequentially 2,4,6-trimethylbenzenamine (0.0022 mol) andN,N-di(methylethyl)ethanamine (0.0024 mol) were added to a solution ofand 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (0.00218mol) in 1,4-dioxane (10 ml). The tube was sealed and the suspension washeated to 120-130° C. in an oil bath while stirring for 90 hours. Themixture was cooled to room temperature. MoreN,N-di(methylethyl)ethanamine (15 ml) was added, and the sample wasreheated to 120-130° C. for 64 hours. The reaction was heated at 150° C.for 6 days. The sample was cooled to room temperature. The sample wasdiluted with ethylacetate and extracted with cold 1M NaOH. The aqueousphase was backwashed with ethylacetate. The combined organic phases weredried and concentrated. Flash column chromatography over silica gel(eluent: CH₂Cl₂). The sample was further purified by preparatory HPLC toyield 0.53 g of4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(54.9%); mp. 220-221° C. (comp. 41).

Example B11

A mixture of 4-aminobenzonitrile (0.0043 mol) and

(0.0021 mol) in 1,4-dioxane (30 ml) was stirred at 100° C. for 16 hours.The solvent was removed by rotary evaporation. The solid residue wastriturated and the residue was dried in vacuo at 40° C. for 16 hours,yielding 0.452 g of

(55%); mp. >300° C. (comp. 43).

Example B12

To a pressure vessel was added

(0.00567 mol), 4-aminobenzonitrile (0.01163 mol) and1-methyl-2-pyrrolidinone (20 ml). The reaction mixture was heated at140° C. for 16 hours. The reaction mixture was cooled to roomtemperature and acetonitrile and water were added. The resultingprecipitate was filtered, and the solid recrystallized with acetonitrileto give 1.27 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-methyl-2-pyrimidinyl]amino]benzonitrile(52); mp. 260-262° C. (comp. 44).

Example B13

Intermediate (11) (0.001 mol) and 2,6-dimethyl-4-aminobenzonitrile(0.00473 mol) were combined and heated to 150° C. while stirring for 16hours. The sample was dissolved in CH₃OH and evaporated onto silica gel(1 g) and eluted with 1:1 hexanes:CH₂Cl₂, 4:1 CH₂Cl₂:hexanes, and neatCH₂Cl₂ (2 L). The desired fractions were evaporated and the residue wasdried in vacuo for 16 hours at 45° C. The thus obtained was transferredto a 4 ml vial in CH₂Cl₂ and the solvent was evaporated, yielding 0.120g of4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(28.6%); mp. 277-280° C. (comp. 45).

Example B14

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile(0.00250 mol) and NH₃/1,4-dioxane 0.5M (0.015 mol) were heated in apressure vessel at 150° C. for 4 days. The sample was allowed to sit atambient conditions for 2 days. Water was added slowly to the mixtureuntil a precipitate formed. The mixture was stirred for 2 hours andfiltered. The solid was recrystallized from CH₃CN to obtain 0.58 g(fraction 1). The filtrate was evaporated (fraction 2). Both fractionswere combined and purified by column chromatography, eluting withCH₂Cl₂. The resulting residue of the desired fraction was recrystallizedfrom CH₃CN to yield 0.44 g of4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile(40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (comp.46).

Example B15

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile(0.000660 mol), tetrahydrofuran (1 ml), and 1-pyrrolidineethanamine(0.00198 mol) were added to a pressure vessel. The mixture was heated at75° C. for 16 hours. CH₂Cl₂ was added, and the mixture was washed withwater, dried, filtered and the filtrate was evaporated. Purificationusing flash column chromatography eluting with 1:9 methanol:methylenechloride produced a solid which was redissolved in CH₃CN.HCl/diethylether 1.0M (0.48 ml) was added, and the mixture was cooled inice. Filtration yielded 0.19 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-[(1-pyrrolidinyl)ethylamino]-2-pyrimidinyl]amino]benzonitrilehydrochloride (1:1) (50.6%); mp. 208-210° C. (comp. 47).

Example B16

To a pressure vessel was added4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile(0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g),tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture wasstirred for 3 days at room temperature, then for 1 day at 75° C., for 1day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). Theliquid was decanted into the reaction flask and the reaction mixture washeated at 110° C. for 3 days. The solvent was evaporated. The residuewas dissolved in CH₂Cl₂, washed with a saturated NaHCO₃ solution andwater, dried (Na₂SO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from CH₃CN, filtered offand dried, yielding 0.15 g of4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]benzonitrile(51%); mp. 185-186° C. The sample was dried (0.2 mm Hg, 80° C., 16hours) (comp. 48).

Example B17

a) n-Butyllithium (2.0 l, 0.005 mol) was added to a 0° C. stirredsolution of 1-(methylethyl)-2-propanamine (0.70 ml, 0.005 mol) andtetrahydrofuran (300 ml). After stirring cold for 30 min, compound (17)(0.005 mol) was added. The resulting mixture was stirred cold for 30 minat which point 1,1-dimethylethyl bromoacetate (1.5 ml, 10 mmol) wasadded and the temperature was allowed to rise to room temperature andthe reaction was stirred for three. In a separate flask n-butyllithium(2.0 ml, 5 mmol) was added to a stirred 0° C. solution of1-(methylethyl)-2-propanamine (0.70 ml, 5 mmol) in tetrahydrofuran (50ml) and allowed to react for 30 min at which time it was transferred tothe room temperature reaction. This procedure was repeated. Quenchedwith 0.5 ml H₂O, the sample was concentrated by rotary evaporation ontosilica gel, and purified by flash chromatography (eluting with 0, 10,20% ethylacetate in hexanes) to give a white solid of

mp. 195-197° C. (comp. 56).

b) A suspension of compound (17) in 40 ml of N,N-dimethylformamide wastreated with 0.24 g of NaH. The effervescent mixture was stirred for 90.A solution of 1,4-dichloro-1,4-butanedione in 10 mlN,N-dimethylformamide was prepared and cooled in an ice bath. Themixture prepared from compound (17) was transferred to the cold solutionof 1(methylethyl)-1-propanamine and was warmed to room temperature withstirring for 42 hours. Another 0.24 g of NaH was added, the reaction wasstirred for 3 days, and diluted with ether and poured into ice.Precipitation was removed by filtration. The 2 phase filtrate wasseparated and the acidic aqueous fraction was extracted twice more withether. The combined ether fractions were washed with small volumes ofdistilled water and dried. The solvent was evaporated and the residuewas subjected to silica gel column chromatography. Reverse phase prepHPLC with immediate cooling for lyophilization of the appropriatefractions provided 0.07 g of

(7.8%); mp. 232-233° C. (comp. 57).

c) To a flask under argon was added NaH 60% and tetrahydrofuran. Thereaction was stirred at room temperature for 10 min and compound (17)added. After stirring for 1 hr ethyl carbonochloridate was added. Thereaction mixture was stirred at room temperature for another 16 hrs andthe solvent evaporated. The residue was partially dissolved indimethylsulfoxide and filtered. The filtrate was purified by reversephase chromatography and lyophilized to give 0.47 g (18%) of

(comp. 58).

d) A mixture of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(0.00147 mol) in ethanoic acid anhydride (10 ml) and 2-propanone (10 ml)was stirred at room temperature for 16 hours. The mixture was thenheated to 55° C., and more ethanoic acid anhydride (3 ml) was added. Themixture was removed from heat after 18 hours and stirred for 6 days atroom temperature. The sample was concentrated by rotary evaporation to asolid. Purification by column chromatography (eluting with 0, 0.5, 1,1.5, 2% (10% NH₄OH in CH₃OH) in methylene chloride) yielded;

mp. 290-295° C. The solid was dried in vacuo for 16 hours at 60° C.(comp. 49).

Example B18

A mixture of4-[[4-(4-cyano-2,6-dimethylphenoxy)-5-nitro-2-pyrimidinyl]amino]benzonitrile(0.0005 mol) in tetrahydrofuran (20 ml) was hydrogenated overnight withPd/C 10% (0.100 g) as a catalyst. After uptake of H₂ (3 equiv; 0.0015mol), the catalyst was filtered off and the filtrate was concentrated byrotary evaporation and dried in vacuo over 16 hours at 40° C., yielding0.15 g of4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile(84%); mp. >300° C. (comp. 50).

Example B19

4-[[4-[(2,4,6-trimethylphenyl)amino]-5-nitro-2-pyrimidinyl]amino]benzonitrile(0.001 mol), Pd/C 10% (0.025 g), ethanol (20 ml), and hydrazine (0.030mol) were combined to form a slurry and stirred at room temperature for16 hours. The solvent was removed by rotary evaporation. The residue wastaken up in tetrahydrofuran (20 ml) and methanol (1 ml). A secondportion of hydrazine (0.5 g) was added, and the reaction was stirred for16 hours at room temperature. A third portion of hydrazine (0.5 ml) wasadded and the reaction was stirred for an additional 16 hours at roomtemperature. The sample was concentrated by rotary evaporation ontosilica gel (1 g) and purified by flash chromatography (eluent: 0.5, 1,2% 10% (NH₄OH in CH₃OH) in CH₂Cl₂). The desired fractions were purifiedby preparatory HPLC to yield 0.24 g of4-[[5-amino-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile(70%); mp. 224-225° C. (comp. 51).

Example B20

Compound (3) (0.001 mol), trimethyl silanecarbonitrile (0.0012 mol),Pd(PPh₃)₂Cl₂ (0.020 g), CuI (0.010 g) and CF₃COOH/H₂O (3 ml) werecombined in a sealed tube and heated to 110° C. for 10 hours. Secondportions of the catalysts Pd(PPh₃)₂Cl₂ (0.020 g) and CuI (0.010 g), andCF₃COOH/H₂O (3 ml) were added and the reaction mixture was stirred for10 hours at 110° C. The material was concentrated by rotary evaporation.The residue was purified by preparative reversed-phase HPLC. The desiredfractions were concentrated and purified by reversed-phase preparativeHPLC and dried with a stream of N₂, then in vacuo at 40° C. for 16hours. Yield: 0.011 g of4-[[5-ethynyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 165-175° C. (comp. 52).

Example B21

Compound (3) (0.000906 mol), tributylphenyl stannane (0.000906 mol),Pd(PPh₃)₄ (0.002718 mol), and 1,4-dioxane (3 ml) were combined under N₂in a sealed tube and heated to 110° C. for 16 hours. The reactionmixture was cooled and concentrated by rotary evaporation. The samplewas purified by Preparatory Reverse Phase HPLC, then dried under Arstream. Drying in vacuo yielded 0.0845 g of or4-[[5-phenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 209-214° C. (comp. 53).

Example B22

Compound (3) (0.001 mol), tetraethenyl stannane (0.22 ml), 1,4-dioxane(2 ml) and Pd(PPh₃)₄ (0.112 g) were combined in a sealed tube under Ar.The mixture was stirred and heated to 100° C. for 16 hours. Moretetraethenyl stannane and Pd(PPh₃)₄ were added. The reaction was placedunder Ar, stirred and heated. The reaction was concentrated by rotaryevaporation and purified on preparative HPLC. The material was driedwith a N₂ stream, and dried under vacuum for 4 hours at 60° C. to obtain0.422 g of4-[[5-ethenyl-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile;mp. 237-242° C. (comp. 54).

Example B23

Compound (3) (0.001225 mol), CuCN (0.001470 mol) andN,N-dimethylformamide (2 ml) were combined in a sealed tube under Argon,then stirred and heated to 160° C. for 16 hours. The residue waspurified by column chromatography (eluent: CH₂Cl₂/hexane 1/1, then pureCH₂Cl₂). The desired fractions were collected and the solvent wasevaporated. The residue was triturated under CH₂Cl₂ at room temperature.The solid was dried (vacuum, 40° C., 24 hours, yielding 0.0864 g of

(24%); mp. 254-259° C. (comp .55). Tables 1, 2, 3 and 4 list compoundsof formula (I-a) which were made analogous to one of the above examples.

TABLE 1

Comp. Ex. No. No. Y Physical data  1 B1a Cl —  2 B1a Br mp. 227-228° C.22 B11 NO₂ mp. 224-226° C.

TABLE 2

Co. Ex. No. No. R^(a) R^(b) R^(c) X Y Q mp./salt 3 B1b CH₃ CH₃ CH₃ NH BrH mp. 227-228° C. 4 B2 CH₃ CH₃ CH₃ NH Cl NH₂ mp. 241-242° C.;trifluoroacetate (1:1) 5 B3 CH₃ CH₃ CH₃ NH Cl H mp. 224-226° C. 6 B5 CH₃CH₃ CH₃ O Cl H mp. 218-219° C. 7 B5 CH₃ CH₃ CH₃ S Cl H mp. 264-266° C. 8B5 CH₃ Br CH₃ O Cl H mp. 237-238° C. 9 B3 CH₃ Br CH₃ NH Cl H mp.217-219° C. 10 B4 Br CH₃ Br NH Cl H mp. 262-263° C. 11 B4 Br Br F NH ClH mp. 200-202° C. 12 B4 CH₃ C(CH₃)₃ CH₃ NH Cl H mp. 214-215° C. 13 B4CH₃ CN CH₃ NH Cl H mp. 281-283° C. 14 B4 Cl Cl CH₃ NH Cl H mp. 243-245°C. 15 B5 Cl Br CH₃ O Cl H mp. 244-247° C. 16 B5 CH₃ Cl CH₃ O Cl H mp.232-235° C. 17 B6 CH₃ CN CH₃ O Br H mp. 288-289° C. 18 B5 CH₃ CN CH₃ OCl H mp. 283-284° C. 19 B7 CH₃ CN CH₃ NH Cl NH₂ mp. 266-268° C.trifluoroacetate (1:1) 20 B3 Cl Cl CH₃ NH Br H mp. 253-254° C. 21 B3 CH₃Br CH₃ NH Br H mp. 243-245° C. 23 B23 CH₃ CN CH₃ NH CN H mp. 275-290° C.trifluoroacetate (1:1) 24 B23 CH₃ Br CH₃ NH CN H mp. 291-299° C. 25 B14CH₃ CN CH₃ O Br NH—CH₃ mp. 248-250° C. 26 B14 CH₃ CN CH₃ O Br NH₂ mp.255-256° C. 27 B14 CH₃ CH₃ CH₃ O Br NH₂ — 28 B14 CH₃ CH₃ CH₃ O Br NH—CH₃mp. 213-214° C. 29 B14 CH₃ CN CH₃ O Br NH—C₂H₅ mp. 263-264° C. 30 B14CH₃ CN CH₃ O Cl NH₂ mp. 272-274° C. 31 B14 CH₃ CH₃ CH₃ O Cl NH₂ mp.199-202° C. 32 B11 CH₃ CH₃ CH₃ NH NO₂ H mp. >300° C. 33 B5 CH₃ CH₃ CH₃ OBr H mp. 207-215° C. 34 B5 CH₃ CH₃ CH₃ O Cl Cl mp. 225-226° C. 35 B5 CH₃CN CH₃ O Cl Cl mp. 273-276° C. 36 B6 CH₃ CN CH₃ O Cl Br mp. 281-282° C.37 B7 CH₃ CH₃ CH₃ O Cl Br mp. 214-215° C. 40 B8 CH₃ CH(CH₃)₂ CH₃ NH Br Hmp. 198° C. trifluoroacetate (1:2) 41 B10 CH₃ CH₃ CH₃ NH Br Cl mp. 220°C. 42 B9 CH₃ CN CH₃ NH Br Cl mp. 259° C. 43 B11 CH₃ CN CH₃ O NO₂ Hmp. >300° C. 44 B12 CH₃ CN CH₃ O Br CH₃ mp. 260° C. 45 B13 CH₃ CN CH₃ NHBr H mp. 277° C. 46 B14 CH₃ CN CH₃ O Br NH₂ mp. 255° C. 47 B15 CH₃ CNCH₃ O Br

mp. 208° C.; HCl (1:1) 48 B16 CH₃ CN CH₃ O Br —NH—O—CH₃ mp. 185-186° C.49 B17d CH₃ CN CH₃ O —NH—COCH₃ H mp. 290-295° C. 50 B18 CH₃ CN CH₃ O—NH₂ H mp. >300° C. 51 B18 CH₃ CH₃ CH₃ NH —NH₂ H mp. 224-225° C.;trifluoroacetate (1:1) 52 B20 CH₃ CH₃ CH₃ NH CN H mp. 165-175° C. 53 B21CH₃ CH₃ CH₃ NH phenyl H mp. 209-214° C. 54 B22 CH₃ CH₃ CH₃ NH —CH═CH₂ Hmp. 237-242° C.; trifluoroacetate (1:1) 55 B23 CH₃ CH₃ CH₃ NH —CH═CH₂ Hmp. 254-259° C.

TABLE 3

Comp. Ex. No. No. Z 38 B17C —C(═O)—CH₃ mp. 194-196° C. 56 B17a—CH₂—CO—O—C(CH₃)₃ mp. 195-197° C. 57 B17b —CH═O mp. 232-233° C. 58 B17e—CO—O—C₂H₅ mp. 209-210° C. 59 B6b —CH₂—CO—OC₂H₅ mp. 185-190° C. 60 B6c—CH₂—O—CO—C(CH₃)₃ mp. 168-169° C. 61 Bbd —CO—CH₂—OCH₂—CO—OCH₃ mp.184-185° C.

TABLE 4

Comp. Ex. No. No. R^(a) R^(b) X Y Q 39 B5 Cl Cl S Br H mp. 198-200° C.

C. Pharmacological Example Example C.1

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%},$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (I-A) were shown to inhibit HIV-1effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 5hereinbelow.

TABLE 5 Co. IC₅₀ CC₅₀ No. (μM) (μM) SI Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 20.030 82.6 2730 10 0.005 0.4 92 3 0.006 4.4 738 11 0.002 0.4 183 1 0.00410.9 2787 12 0.020 48.5 2393 4 0.002 10.0 5555 13 0.0005 0.4 860 5 0.0020.4 178 14 0.002 0.4 191 6 0.009 >100 >11049 15 0.010 >100 >9661 70.084 >100 >1182 16 0.010 >100 >10416 8 0.012 >100 >8298 170.002 >10 >6451 9 0.003 1.2 376 18 0.001 >10 >7142 46 0.002 >200 >7142860 0.002 74.52 39223 61 0.002 >100 >52631

The invention claimed is:
 1. A compound having the formula

a N-oxide, an addition salt, or a stereochemically isomeric formthereof, wherein -b¹=b²-C(R^(2a))=b³-b⁴= represents a bivalent radicalof formula—N═CH—C(R^(2a))═CH—CH═  (b-2);—CH═N—C(R^(2a))═CH—CH═  (b-3);—N═CH—C(R^(2a))═N—CH═  (b-4);—N═CH—C(R^(2a))═CH—N═  (b-5);—CH═N—C(R^(2a))═N—CH═  (b-6);—N═N—C(R^(2a))═CH—CH═  (b-7); q is 0, 1, 2 or 3; R¹ is hydrogen; aryl;formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkylcarbonyloxy; C₁₋₆alkyloxyC₁₋₆alkylcarbonyl substituted withC₁₋₆alkyloxycarbonyl; R^(2a) is cyano, aminocarbonyl, mono- ordi(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano, aminocarbonylor mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano,or C₂₋₆alkynyl substituted with cyano; each R² independently is hydroxy,halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one ormore halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,—NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶or a radical of formula

wherein each A independently is N, CH or CR⁶; B is NH, O, S or NR⁶; p is1 or 2; and R⁶ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₃₋₇cycloalkyl, whereby each of said aliphatic group may be substitutedwith one or two substituents independently selected from C₃₋₇cycloalkyl,indolyl or isoindolyl, each optionally substituted with one, two, threeor four substituents each independently selected from halo, C₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino,polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl, phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of saidaromatic rings may optionally be substituted with one, two, three, fouror five substituents each independently selected from the substituentsdefined in R²; or L is —X—R³ wherein R³ is phenyl, pyridinyl,pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromaticrings may optionally be substituted with one, two, three, four or fivesubstituents each independently selected from the substituents definedin R²; and X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)— or —S(═O)₂—; Q represents hydrogen, C₁₋₆alkyl, halo,polyhaloC₁₋₆alkyl or —NR⁴R⁵; and R⁴ and R⁵ are each independentlyselected from hydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy,C₁₋₁₂alkylcarbonyl, C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- ordi(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein eachof the aforementioned C₁₋₁₂alkyl groups may optionally and eachindividually be substituted with one or two substituents eachindependently selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy,carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- ordi(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, aryl and Het; or R⁴ and R⁵ takentogether may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono-or di(C₁₋₁₂alkyl)aminoC₁₋₄-alkylidene; Y represents hydroxy, halo,C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or morehalogen atoms, C₂₋₆alkynyl optionally substituted with one or morehalogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶,C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono-or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or aryl; aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;Het is an aliphatic or aromatic heterocyclic radical; said aliphaticheterocyclic radical is selected from pyrrolidinyl, piperidinyl,homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl andtetrahydrothienyl wherein each of said aliphatic heterocyclic radicalmay optionally be substituted with an oxo group; and said aromaticheterocyclic radical is selected from pyrrolyl, furanyl, thienyl,pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of saidaromatic heterocyclic radical may optionally be substituted withhydroxy.
 2. A compound as claimed in claim 1 wherein R¹ is hydrogen,aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl,C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyloxycarbonyl.
 3. A compound as claimed in claim 1 wherein L is—X—R³ wherein R³ is 2,4,6-trisubstituted phenyl.
 4. A compound asclaimed in claim 1 wherein Y is cyano, —C(═O)NH₂ or a halogen.
 5. Acompound as claimed in claim 1 wherein Q is hydrogen or NR⁴R⁵.
 6. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically active amount of a compound as claimed inclaim
 1. 7. A process for preparing a compound as claimed in claim 1,comprising a) reacting an intermediate of formula (II) with an aminoderivative of formula (III) under solvent-free conditions or in areaction-inert solvent under a reaction-inert atmosphere

 wherein W¹ is a suitable leaving group and L, Y, Q, R¹, R², R^(1a), qand -b¹=b²-C(R^(2a))=b³-b⁴= are as defined in claim 1; b) reacting anintermediate of formula (IV) with an intermediate of formula (V) undersolvent-free conditions or in an appropriate solvent under areaction-inert atmosphere

 wherein W² is a suitable leaving group and Y, Q, R¹, R², R^(2a), R³, qand -b¹=b²-C(R^(2a))=b³-b⁴= are as defined in claim 1; c) reacting anintermediate of formula (IV) with an intermediate of formula (VI) in anappropriate solvent under a reaction-inert atmosphere in the presence ofa suitable base

 wherein W² is a suitable leaving group and Y, Q, R¹, R², R^(2a), R³, qand -b¹=b²-C(R^(2a))=b³-b⁴= are as defined in claim 1; or optionallyconverting compounds of formula (I-a) into each other followingart-known transformation reactions; and further, if desired, convertingthe compounds of formula (I-a), into an acid addition salt by treatmentwith an acid, or conversely, converting the acid addition salt form intothe free base by treatment with alkali; and optionally preparingstereochemically isomeric forms thereof.
 8. The combination of acompound as defined in claim 1 and another antiretroviral compound.
 9. Aproduct containing (a) a compound as defined in claim 1 and (b) anotherantiretroviral compound, as a combined preparation for simultaneous,separate or sequential use in anti-HIV treatment.
 10. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and asactive ingredients (a) a compound as defined in claim 1 and (b) anotherantiretroviral compound.